The maintenance of immunological homeostasis is one of the fundamental requirements for keeping good health. Upon considering “what is the immunological homeostasis in health”, an important understanding is that environmental factors largely affect functional expression of immune-related genes, i.e., differentiation and functional maturation of immune-responsive cells.
The digestive tract, covering the area about 200 times as large as that of skin, is primary interface exposed to the external environment. Therefore, enteric bacteria and food ingredients, which are representatives of the external environment in the digestive tract, are primary quantitative and qualitative environmental factors for the living body. Since the digestive tract is always exposed to a large amount of various non-self antigens and innate immune signals, it is the forefront of the bio-defense system against the majority of external immune signals, and naturally, the majority of immune related cells in the body can be found in the intestine.
In conjunction with that fact, a biological response to the enteric environment may be reflected on a rapid increase in immune diseases, typically including such as food allergy and inflammatory bowel diseases such as large-intestinal ulcer. Interestingly, it extends to other types of allergies and autoimmune diseases such as type I diabetes, which are remarkably increasing and become social issues in late years (see Kalliomaki M. et al., Lancet, 2001; 357: 1076, Stene L C and Nafstad P, Lancet, 2001; 357: 607-8).
Here, for the maintenance of immunological homeostasis, immunoregulatory cells are important. Among cell groups responsible for the balance of immunological responses, the term “immunoregulatory cells” is a generic term for a cell group that builds up a so-called self-defense mechanism for controlling an excessive immune response. In recent years, the differentiation and functional maturation mechanisms of immunoregulatory cells has gradually being clarified. In particular, it becomes clear that such mechanisms are effectively induced in the intestine (see Tsuji N. M. et al., Immunology, 2001; 458, Int. Immunol., 2003; 103: 15: 525).
As described above, a great number of environmental factors can be found in the digestive tract, and the immunoregulatory cells are responsible for avoiding an excessive response to these external antigens. Therefore, an attention has been paid thereto in the anticipation that the analysis of induction mechanisms of immunoregulatory cells in the intestine will lead to the development of technology for prevention or treatment of immune diseases.
It has become clear that the digestive tract is in an environment suitable for tolerance induction and many lymphocytes existent in the digestive tract are in an activated state. Therefore, if immunoregulatory cells are “positively” induced in the digestive tract and activated for the maintenance of immunological homeostasis, intestinal environmental should include factors that support such a phenomenon.
It is known that the digestive tract is rich in regulatory cytokines including Interleukin-10 (IL-10) and TGF-β. Also the present inventors have already revealed that Interleukin (IL-18) is an important environmental element for the induction of intestinal regulatory T cells (see Proceedings of the 32nd Annual Meeting of the Japanese Society for Immunology, 2002:256, Tsuji N M and Nowak B Ann NY Acad Sci (oral tolerance) 2004: in press).
To date, the development of medicines which induce immunoregulatory cells has been under way on the assumption that a chemical substance such as dexamethasone exerts such function (see Barrat F. J. et al., JEM, 2002; 195: 603).
On the other hand, a search for a microorganism and an ingredient thereof that induce immunoregulatory cells in the digestive tract has been in progress by the present inventors. In particular, if there is a microorganism which has been already used as an ingredient for food products, it can be orally administered without any problem in safety, like in the case of a chemical substance such as dexamethasone. Therefore, it can be also expected to be applied as so-called probiotics (living microorganisms that act profitably on hosts to keep them healthy) to food products for the prevention or treatment of immune diseases.
In general, among microorganisms, lactic acid bacteria are highly safe as representative probiotics and have accumulated experiences in industrial applications of food products, such as the production of fermentative food products and biodegradable resins. Besides, lactic acid bacteria have been known to exert various physiological effects based on the functionalities of lactic acid bacteria, such as the action of controlling the functions of the intestines, the action of lowering serum cholesterol levels, and the action of immunological activation when the lactic acid bacteria are taken in the body in the form of fermented milk (see Fuller, R., J. Appl. Bacteriol., 1989; 66: 365).
However, studies on microorganism and the ingredient thereof that induce immunoregulatory cells have just begun but no search and evaluation methods therefor have been established. Therefore, the microorganism and the ingredient thereof that induce immunoregulatory cells have not been found so far in lactic acid bacteria either.